Participation of protein kinases in staurosporine‐induced interleukin‐6 production by rat peritoneal macrophages

The incubation of rat peritoneal macrophages in the presence of staurosporine, a non‐specific protein kinase inhibitor, induced interleukin‐6 (IL‐6) production in a time‐ and concentration‐dependent manner at 6.3–63 n M , but at 210 n M , the stimulant effect on IL‐6 production was reduced. The levels of IL‐6 mRNA as determined by a reverse transcription‐polymerase chain reaction were also increased by staurosporine in parallel with the ability to induce IL‐6 production. Compounds structurally related to staurosporine including K‐252a (non‐specific protein kinase inhibitor) and KT‐5720 (inhibitor of cyclic AMP‐dependent protein kinase, PKA), did not increase IL‐6 production by peritoneal macrophages. Staurosporine‐induced increases in IL‐6 production and expression of IL‐6 mRNA were decreased by the PKC inhibitors, H‐7 (2.7–27 μ M ), Ro 31–8425 (1–10 μ M ) and calphostin C (0.3–3 μ M ) and by the phosphatidylinositol 3‐kinase (PI 3‐kinase) inhibitor LY294002 (30–100 μ M ), but were further increased by the protein tyrosine kinase (PTK) inhibitor, genistein (12–37 μ M ). The staurosporine‐induced increase in IL‐6 production was not affected by the PKA inhibitor, H‐89 (0.1–3 μ M ). These findings suggest that the induction of IL‐6 production by staurosporine is secondary to elevation of IL‐6 mRNA level, which, in turn, is positively regulated by the activation of PKC and PI 3‐kinase and negatively regulated by the activation of PTK. PKA does not appear to play a significant role.British Journal of Pharmacology (1999) 127 , 1309–1316; doi: 10.1038/sj.bjp.0702659